Human interferon-gamma (IFN-.gamma.) is a natural human immunoregulatory protein. It has been established as an agent effective in the treatment of tumors and virus infections in humans. The precise mechanisms by which IFN-.gamma. inhibits virus and tumor growth in vivo remain unknown. There is evidence that IFN-.gamma. works by at least one of two mechanisms: (1) by acting directly on the virus infected cell and the tumor cell and/or (2) by first activating cells of the immune system which then destroy the virus-infected cell or tumor cell [Interferons and other Regulatory Cytokines, E. De Maeyer and J. De Maeyer-Guignard, John Wiley & Sons, New York (1988)].
One manifestation of a stimulated immune system is the enhanced expression on the surface of immune cells of the proteins of the Major Histocompability Complex (MHC). The MHC is made of class I, II, and III genes that code for the respective class I, II, and III proteins. Class I and II proteins reside on the cell surface and are involved in controlling the immune response, whereas the class III proteins appear in the serum and are not involved in controlling the immune response. Class I and II proteins on antigen presenting cells e.g. monocytes, B lymphocytes, dendritic cells, present foreign antigens to T lymphocytes with subsequent destruction of the cell containing the foreign antigen. The enhanced expression of the class I and II proteins is essential for the immune system to rid an animal of virus-infected cells and enhance specific antibody production. IFN-.gamma. is one of the major regulators of the immune response due to its ability to enhance the expression of MHC class I and II proteins. An example of the benefit of MHC I enhancement by IFN-.gamma. is the enhancement of class I proteins on virus-infected cells. The virus infected cell presents synthesized viral antigens on its cell surface to the T cell receptor on cytotoxic T cells (CD4 cells) with the subsequent destruction of the virus infected cell by the cytotoxic T cell. An example of the benefit of MHC II enhancement by IFN-.gamma. is the enhancement of class II proteins on monocytes. Monocytes can ingest invading microorganisms and the class II proteins on the monocyte surface present peptides derived from the invading microorganism. These peptides held by the class II proteins are presented to the T cell receptor on helper T cells (CD8) with subsequent secretion of lymphokines by the CD8 cell. The secreted lymphokines cause proliferation of the antibody synthesizing B lymphocytes which synthesize large amounts of antibody against the invading microorganism.
It can be seem from the above examples that a compound that enhances the IFN-.gamma. induction of MHC molecules would be useful in combination with IFN-.gamma. for the treatment of infections by microorganisms. Such a compound might permit a reduction in the dose of IFN-.gamma., thereby advantageously giving the same therapeutic effect as with IFN-.gamma. alone but with fewer of the IFN-.gamma. related side effects.
There are at least three reports of compounds that potentiate the IFN-.gamma.-induced MHC expression [Coutinho, G. C., Dudrieu-Trautmann, O., Strosberg, A. D., and Couraud, P. O., Catecholamines Stimulate the IFN-.gamma.-induced Class II MHC Expression on Bovine Brain Capillary Endothelial Cells, J. Immunol., 147, 2525-2529 (1991); Zhu, J., Mix, E., Olsson, T., and Link, H., "Influence of Ion Channel Modulation of in Vitro Interferon-.gamma. Induced MHC Class I and II Expression on Macrophages", Immunopharmacology and Immunotoxicology, 17, 109-136 (1995); Mothes, T., Bendix, U.,, Pfannschmidt, C.,, and Lehmann, I., "Effect of Gliadin and Other Food Peptides on Expression of MHC Class II Molecules by HT-29 Cells", Gut, 36, 548-552 (1995)].